The present invention relates to the A ring part of vitamin D derivatives, intermediates for synthesizing them and a process for preparing them.
More particularly, the present invention relates to the A ring part of vitamin D derivatives having a 3-hydroxypropyloxy group at the 2xcex2-position, intermediates for synthesizing them and a process for preparing them.
Recently, some of the physiological activities of vitamins D have been revealed. It is known that a certain vitamin D, for example, 1xcex1,25-dihydroxy vitamin D3, exhibits a variety of physiological activities such as a calcium metabolism-controlling activity, proliferation-inhibiting and differentiation-inducing activities on cells such as tumor cells and an immune-controlling activity. However, 1xcex1,25-dihydroxy vitamin D3 disadvantageously causes hypercalcemia depending on the dose and/or the administration route and thus is not suitable for use as an antitumor agent, an anti-rheumatic agent, etc.
In order to isolate such activities of the vitamin D derivatives, numerous vitamin D derivatives have been synthesized recently and their physiological activities evaluated. For example, the synthesis of vitamin D3 derivatives which have a substituent at the 2xcex2-position is described in, for example, Japanese Patent Publication (Kokoku) No. 3-14303, Japanese Patent Publication (Kokai) No. 61-267549 and Japanese Patent Publication (Kokai) No. 6-41059. Some of those vitamin D3 derivatives which have a substituent at the 2xcex2-position exhibit calcium metabolism-controlling activity in vivo and differentiation-inducing activity on cells such as tumor cells and are known to be useful as a medicine, such as a therapeutic agent for diseases associated with abnormal calcium metabolism (e.g., osteoporosis, osteomalacia, etc.) and an antitumor agent. Among them, 2xcex2-(3-hydroxypropoxy)-1xcex1,25-dihydroxy vitamin D3 is expected to be of practical use in treating osteoporosis, with a high blood level being able to be maintained for a long duration.
In synthesizing such vitamin D derivatives having a specific substituent at the 2-position, a process is known in which the A ring structure of a steroid compound, a starting material, is epoxylated and then cleaved so as to introduce the substituent to the 2-position (Japanese Patent Publication (Kokai) No. 61-267549; Chem. Pharm. Bull. 41(6), 1111-1113 (1993)). This process, however, has some disadvantages, such as difficulty in obtaining the raw material and low yield of the last step, i.e., light irradiation/thermal isomerization.
According to another known process for synthesizing the vitamin D3 derivatives, the A ring part and the CD ring part of the vitamin D derivatives are synthesized separately and then coupled. Japanese Patent Publication (Kokai) No. 6-25039 discloses an A ring part of vitamin D derivatives and a process for synthesizing the A ring part. However, this process requires a considerably large number of reaction steps to synthesize the desired A ring part from a starting material. In addition, it is not suitable for synthesizing, for example, 2-(3-hydroxypropoxy)-1xcex1,25-dihydroxy vitamin D3, because a specific group cannot be introduced to the 2xcex2-position by this process.
One object of the present invention is to provide compounds corresponding to the A ring part of vitamin D derivatives which have a substituent at the 2-position.
Another object of the present invention is to provide intermediates useful for the synthesis of the compounds of the present invention corresponding to the A ring part.
Still another object of the present invention is to provide a process for preparing the compounds of the present invention corresponding to the A ring part.
As a result of careful studies as to whether such vitamin derivatives that have a substituent at the 1-, 2- or 3-position stereochemically selectively can be synthesized by utilizing optically pure sugars, the inventors of the present invention have found that an A ring part having a substituent at a desired stereochemical conformation can be obtained by using D-mannitol as the starting material and thereby completed the present invention. Since D-mannitol is a low price sugar and readily available, the process of the present invention is expected to be applicable to the production of vitamin D derivatives on an industrial scale.
According to a first aspect of the present invention, there are provided compounds of the general formula (1): 
(wherein R1, R2 and R3, which may be the same or different, represent a hydrogen atom or a protecting group and R4 represents a lower alkyl group).
Preferably, R4 in the general formula (1) is methyl.
According to a second aspect of the present invention, there are provided compounds of the general formula (2): 
(wherein R1, R2 and R3, which may be the same or different, represent a hydrogen atom or a protecting group; and R5 represents a hydrogen atom or a lower alkoxycarbonyl group).
Preferably, R5 in the general formula (2) is a methoxycarbonyl group.
According to a third aspect of the present invention, there are provided compounds of the general formula (3): 
(wherein R1 and R2, which may be the same or different, represent a hydrogen atom or a protecting group).
The compounds of the general formulae (2) and (3) are intermediates for synthesizing the compounds of the general formula (1) of the present invention.
Japanese Patent Application No. 9-53316 (published as Japanese Patent Publication (Kokai) No. 10-251183 on Sep. 22, 1998 after the priority date of the present application) filed by the applicant of the present application discloses an epimer mixture of a compound having the same structure as the general formula (3) except for the stereochemical conformation. As is mentioned in the above, the present invention is aimed at synthesizing compounds corresponding to the A ring part of vitamin D derivatives, which are optically pure from the viewpoint of the positional and the stereochemical selectivity, without producing epimers by using an optically pure sugar, i.e. D-mannitol. However, the compounds of the general formulae (1) to (3) are novel and processes for synthesizing those compounds are not limited to a certain process. For example, the compounds of the general formula (3) of the present invention having a specific stereochemical conformation is theoretically obtainable by means of column chromatography, etc. from an epimer mixture of the compound disclosed in Japanese Patent Application No. 9-53316, that has the same structure as the compounds of the general formula (3) except for the stereochemical conformation. Compounds obtainable from such procedures are also included in the scope of the present invention. In addition, it is also possible to synthesize such vitamin D derivatives by coupling a compound corresponding to the CD ring part to a compound of the general formula (2) (wherein R5 is H).
According to a fourth aspect of the present invention, there is provided a process for producing a compound of the general formula (1): 
(wherein R1, R2 and R3, which may be the same or different, represent a hydrogen atom or a protecting group and R4 represents a lower alkyl group) comprising:
(a) reacting a compound of the general formula (3): 
(wherein R1 and R2, which may be the same or different, represent a hydrogen atom or a protecting group) with a metal acetylide to obtain a compound of the general formula (2): 
(wherein R1, R2 and R3, which may be the same or different, represent a hydrogen atom or a protecting group; and R5 represents a hydrogen atom);
(b) reacting the compound of the general formula (2) with a lower alkyl halogenated carbonate to obtain a compound of the general formula (2) (wherein R1, R2 and R3, which may be the same or different, represent a hydrogen atom or a protecting group; and R5 represents a lower alkoxycarbonyl group); and
(c) subjecting the compound of the general formula (2) obtained in the step (b) to a reaction of ring formation.
Detailed mode of the present invention and specific examples for carrying out the present invention will be explained below.
In the description of the present application, R1, R2 and R3, which may be the same or different, represent a hydrogen atom or a protecting group. xe2x80x9cProtecting groupxe2x80x9d refers a group protecting a hydroxy group and includes any protecting groups removable by conventional deprotecting means (e.g., hydrolysis, oxidative cleavage, reductive cleavage or hydrogenlysis) without substantially giving harmful effect to other portions of the molecule.
Examples of the protecting groups are as follows:
(I) an acyl group represented by RaCOxe2x80x94 (wherein Ra is a hydrogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group or a C6-C30 aryl group); for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, caproyl, benzoyl, trifluoroacetyl, etc.;
(II) an alkoxycarbonyl group represented by RbOCOxe2x80x94 (wherein Rb is a C1-C6 alkyl group, a C1-C6 alkenyl group, a C7-C9 aralkyl group, or a C6-C30 aryl group); for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, phenoxycarbonyl, etc.;
(III) a trisubstituted silyl group represented by the following formula: 
(wherein Rd, Re and Rf, which are the same or different, represent a C1-C6 alkyl group, a C6-C30 aryl group or a C7-C9 aralkyl group); for example, trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, etc.;
(IV) an 1-alkoxy or 1-mercaptoalkyl group represented by the following formula: 
{wherein X represents an oxygen atom or a sulfur atom and Rg and Rgxe2x80x2 each represent a hydrogen atom or a C1-C6 alkyl group; Rh is a substituted or unsubstituted C1-C6 alkyl group [examples of the substituent are a lower alkoxy group, a halogen atom (e.g. chlorine), an alkyl substituted silyl group (e.g. trimethylsilyl group) and a phenyl group which may be substituted with an alkoxy group, a halogen atom, etc.]}; for example, methoxymethyl, methoxyethoxymethyl, 1-ethoxyethyl, methoxyisopropyl, methylthiomethyl, t-butylthiomethyl, xcex2-trichloroethyloxymethyl, trimethylsilylethoxymethyl, p-methoxybenzyloxymethyl, p-chlorobenzyloxymethyl, etc.;
(V) an 2-oxacycloalkyl group represented by the following formula: 
(wherein n is an integer of 3 to 6); for example, a tetrahydrofuranyl group, a tetrahydropyranyl group, etc.; and
(VI) an aralkyl group such as a benzyl group.
In the general formula (1) of the present application, R4 represents a lower alkyl group. The carbon number of the lower alkyl group is generally 1 to 6, preferably 1 or 2 and more preferably 1.
In the general formula (2) of the present application, R5 represents a hydrogen atom or a lower alkoxycarbonyl group. The carbon number of the lower alkyl moiety of the lower alkoxycarbonyl group is generally 1 to 6, preferably 1 or 2 and more preferably 1. In other words, when R5 is a lower alkoxycarbonyl group, R5 is preferably a methoxycarbonyl group or an ethoxycarbonyl group.
Compounds of the general formula (1) of the present invention can be synthesized from a compound of the general formula (3) via a compound of the general formula (2); the synthesis process and the compounds of the general formulae (2) and (3) also form one aspect of the present invention, as is mentioned in the above.
Compounds of the general formula (3) of the present invention can be synthesized, for example, according to the following reaction scheme 1 using D-mannitol as a starting material. 
The compound 2 (2,5-anhydro-4,6-di-O-benzoyl-1,3-O-isopropylidene-D-glucitol) in the reaction scheme 1 is a known compound and is synthesizable from D-mannitol by the process described in, for example, Azeez M. Mubarak et al. J. C. S. Perkin I (1982), p.809-814 (the process shown in the above reaction scheme 1 is a modification of this process). In the following Examples of the present application, the compound 2 is used as the starting material. Acidic conditions of the process for forming a tetrahydrofuran ring from sugars such as D-mannitol is discussed by R. Barker in J.Org.Chem. (1970) Vol. 35, No. 2, p.461-464 and stereochemistry of the skeleton structure of the compound 2 is discussed by Theodore A. W. Koerner, Jr. et al. in Carbohydrate Research, (1977) 59, p.403-416. Both of these documents relate to a process for synthesizing compounds of the reaction scheme 1 from D-mannitol and the content of these documents is incorporated into this application by reference.
In the reaction scheme 1, the compound 4 is synthesized by selectively removing and changing the protecting groups of the compound 2. In the compound 4, only a hydroxy group that is to be at the 2-position of a vitamin D derivative when the compound 4 is synthesized as the A ring part of the vitamin D derivative is deprotected. By reacting such a compound with the compound 5 (3-benzyloxy-1-methanesulfonyloxypropane), a compound corresponding to the A ring part of vitamin D derivatives, which have a specific substituent at 2-position selectively in position and stereochemistry, can be synthesized.
3-Benzyloxy-1-methanesulfonyloxypropane refereed as the compound 5 in the reaction scheme 1 forms the 2-position substituent of the vitamin D derivatives and can be synthesized from a starting material such as 3-benzyl-oxypropanol (a known compound described by M. J. Martinelli, J. Org. Chem. 1990, 55, 5065-5073) by substituting the hydrogen atom of the hydroxy group, for example, according to a process described in Example 1.
The compound 4 is reacted with the compound 5 to give the compound 6 which is to be appropriately deprotected and protected to give the compound 8. Details of the process, conditions, etc. for deprotection and protection are known in this technical field and thus those skilled in the art can appropriately select such a process, conditions, etc.
The compound 8 can be obtained by appropriately deprotecting and protecting the compound 6 obtained by reacting the compound 4 with the compound 5. Details of the method, conditions, etc. for deprotection and protection are known in this technical field and those skilled in the art can appropriately select such a method, conditions, etc.
Then the compound 9 can be obtained by subjecting the compound 8 to a reaction of ring cleavage. The ring cleavage can be carried out by a 2-step reaction as shown in Example 7 to be described later: first, the compound 8 is reacted with an appropriate metallic halogenated compound, such as lithium iodide (LiI), sodium iodide, potassium iodide and cesium iodide, in the presence of an ether such as tetrahydrofuran (THF) or a hydrocarbon such as benzene, toluene and hexane; then reacted with activated zinc and the like in the presence of an appropriate solvent (e.g., a mixture of carboxylic acids such as acetic acid and alcohols such as ethanol or water). Alternatively, the ring cleavage can be proceeded by reacting the compound 8 with solely samarium iodide (II) (SmI2) in the presence of a solvent such as ethers (e.g., tetrahydrofuran (THF)), alcohols (e.g., ethanol), water and the like.
Then, the compound 10 is obtained by epoxylating the terminal moiety of the compound 9; the compound 11 is obtained by protecting the hydroxy group of the compound 10. The compounds 10 and 11 are novel and both of them have a basic skeleton represented by the general formula (3).
The compound 11 is an intermediate for synthesizing the compounds of the present invention having the general formula (1); the following reaction scheme 2 shows an example process for synthesizing the compound 16 from the compound 11. The compound 16 is included in the compounds of the present invention having the general formula (1). 
First, for obtaining the compound 12, the compound 11 is subjected to reaction with a metallic acetylide such as lithium acetylide, sodium acetylide and potassium acetylide (preferably such a metallic acetylide is used in a complex form with ethylenediamine and the like) in an appropriate solvent such as DMSO at xe2x88x9210xc2x0 C.xcx9c20xc2x0 C., preferably at 0xc2x0 C.xcx9c1020  C., or with a metallic acetylide such as lithium acetylide, sodium acetylide and potassium acetylide in an appropriate solvent such as an ether (e.g., THF) or a hydrocarbon (e.g., benzene, toluene and hexane) in the presence of a Lewis acid such as boron trifluoride.diethyl ether, etc. Then, the compound 14 is obtained by appropriately removing or adding protecting groups. The compound 15 can be obtained as follows: after subjecting compound 14 to reaction with a metallic alkyl (e.g., n-butyl lithium, s-butyl lithium, etc.) or a metallic alkyl halogenated compound (e.g., methyl magnesium iodide, ethyl magnesium bromide, etc.), the terminal moiety of the resulting compound is alkoxycarbonylated by reaction with a halogenated carbonic acid ester (e.g., methyl chlorocarbonate (ClCO2CH3), ethyl chlorocarbonate, etc.) in the presence of a preferred solvent (e.g., THF, diethyl ether, etc.), generally at a temperature ranging from xe2x88x92100xc2x0 C. to xe2x88x9250xc2x0 C., preferably from xe2x88x92100xc2x0 C. to xe2x88x9270xc2x0 C.
Finally, the compound 15 is subjected to a reaction of ring formation to give the compound 16 corresponding to the A ring part of vitamin D derivatives. Although a specific example of the ring formation is shown in Example 14, it is apparent that the ring formation can be carried out under other preferred conditions. In general, the ring formation can be carried out by reacting compound 15 in an appropriate solvent (e.g., benzene, toluene, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, hexane, etc.) at a temperature ranging from 20xc2x0 C. to 80xc2x0 C., preferably from 30xc2x0 C. to 60xc2x0 C. in the presence of 0 valent palladium (e.g., tetra(triphenylphosphine)palladium (0), tris(dibenzylidene acetone)(chloroform)dipalladium (0), etc.) or divalent palladium (e.g., palladium acetate (II), dichlorobis(triphenylphosphine)palladium (II), etc.) and a preferable ligand (e.g., triphenylphosphine, tris(o-tolyl)phosphine, tirmethylphosphite, 1,2-bis(diphenyl-phosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 1,1xe2x80x2-bis(diphenyl-phosphino)ferrocene, N,Nxe2x80x2-bis(benzylidene)ethylenediamine (BBEDA), etc.) and a preferred addition product (e.g., acetic acid, pivalic acid, hydoroquinone, ammonium formate, etc.).